Various medical conditions are caused, exacerbated, and/or characterized by unwanted inflammation. For example, chronic inflammation is central to the development of a variety of acute organ failures, including those involving the heart, kidney, lung, and brain. Chronic inflammation is also a major contributing factor to chronic organ dysfunction, including those involving the heart and kidney as well as diabetes type 2. Several of these conditions, such as, for example, chronic heart failure (CHF) and acute decompensated heart failure (ADHF), through abnormal or excessive chronic activation of the immune system, may result in life threatening myocardial dysfunction.
Certain cell types are critical to the dysfunction of the cardiovascular and immune systems. For example, leukocytes such as neutrophils contribute to the pathogenesis and progression of various inflammatory conditions, including systemic inflammatory response syndrome (SIRS), sepsis, ischemia/reperfusion injury, acute respiratory distress syndrome (ARDS), CHF, and ADHF (see, e.g., Kaneider et al. (2006) FEBS J 273:4416-4424; Maroszynska et al. (2000) ANN. TRANSPLANT. 5(4):5-11). Other types of leukocytes, such as monocytes and tissue macrophages, have been identified as critical sources of systemic inflammation in CHF and cause a decrease in cardiac myocyte contractility (see, e.g., Conraads et al. (2005) J. HEART LUNG TRANSPLANT. 24(7): 854-59; Simms et al. (1999) AM. J. PHYSIOL. 277: H253-60; Conraads et al. (2005) J. HEART LUNG TRANSPLANT, 24(7): 854-9; Simms et al. (1999) AM. J. PHYSIOL. 277: H253-60). In addition, activated platelets enhance leukocyte adhesion and promote leukocyte activation. While inflammation and a systemic immune response can be beneficial in certain circumstances, they can also be fatal.
Inflammatory injury in organs can result in microvascular damage induced by leukocyte activation and aggregation, as well as platelet activation and aggregation. These activated cells can contribute to microvascular stasis and reperfusion injury by releasing toxic compounds into a patient's tissue. Activated leukocytes additionally cause damage by extravasating across the endothelium into the tissue, where they release toxic agents normally intended to destroy invading microbes or clear out necrotic debris. Further, the interaction of activate leukocytes and the endothelium can lead to increased vascular permeability with fluid leakage from the intravascular space to the tissue interstitium with resulting hypovolemia, hypotension, and cardiovascular instability. Activated platelets additionally cause damage by enhancing the activation and endothelial transmigration of leukocytes. When these processes are not controlled, they can lead to tissue injury and death.
Cardiovascular disease is the leading cause of mortality in the United States, accounting for 45% of all deaths. Furthermore, in the United States, CHF affects 5 million people, with over 0.5 million new cases identified annually with direct hospital costs exceeding $30 billion (see, e.g., Association (2006) HEART DISEASE AND STROKE FACTS; Association (2002) 2003 HEART AND STROKE STATISTICAL UPDATE; Fonarow et al. (2003) 4: p. S21-30). In severe CHF, annual mortality rates can be as high as 50%. Currently, treatment of CHF generally involves a ventricular assist device or orthotropic heart transplant. Over the past decade, a number of therapeutic agents for treating CHF have been clinically tested in large prospective trials. Endothelin receptor antagonists, adenosine A1-receptor antagonist, and vasopressin V2 receptor blocker have all failed to prove clinical efficacy (see, e.g., McMurray et al. (2007) JAMA 298(17): 2009-19; Massie et al. (2010) N. ENGL. J. MED. 363(15): 1419-28; Konstam et al. (2007) JAMA 297(12): 1319-31). The myocardial calcium sensitizing agent (levosimendan) and the vasodilatory recombinant B-type natriuretic peptide (niseritide) have also failed to meet clinical efficacy end points with an increase in risks of arrhythmias or hypotension ((see, e.g., Cohn et al. (1998) N. ENGL. J. MED. 339(25): 1810-6; Mebazza et al. (2007) JAMA 297(17): 1883-91; O'Connor et al. (2011) N. ENGL. J. MED. 365(1): 32-43).
Acute decompensated heart failure (ADHF) accounts for almost one million hospitalizations per year, and rehospitalization within six months is as high as 50%. The annual mortality rate in patients frequently hospitalized with ADHF approaches 50%. Current therapeutic approaches for treating patients with ADHF focus on relieving these patients of the congestive symptoms of heart failure, usually with diuretics. However, such an approach results in, and is limited by further declines in renal functions.
Accordingly, there remains a need for improved treatments of inflammatory conditions that affect myocardial functions, such as chronic heart failure and acute decompensated heart failure.